Risperidone sustained release microsphere composition

ABSTRACT

A risperidone sustained release microsphere formulation is provided. The microsphere formulation includes risperidone or 9-hydroxy risperidone or salts thereof, and a polymer blend having a first uncapped lactide-glycolide copolymer and a second uncapped lactide-glycolide copolymer, in which the first uncapped lactide-glycolide copolymer is a copolymer with a high intrinsic viscosity and the second uncapped lactide-glycolide copolymer is a copolymer with a low intrinsic viscosity. The sustained release micro sphere formulation according to an embodiment of the present disclosure is suitable for large-scale industrialized production with improved stability, the in vivo release behavior of which will not change after long-term storage.

FIELD

The present disclosure belongs to pharmaceutical preparation field, andmore particularly relates to a risperidone long-acting sustained releasemicrosphere composition, method for preparing the same and use of thesame;

BACKGROUND

Schizophrenia is a serious disabling mental disorder. With thedevelopment of intense social competition, quick pace of life andchanges in family structure, people face greater pressure than before,and consequently mental health problems become more and more prevalent.Schizophrenia is the most common disease in mental disorder. According tstatistics, the prevalence of schizophrenia in China is 6.55%, there aremore than 7.8 million schizophrenes, and the global disease rate is ashigh as 1.5%.

Antipsychotic drugs, also referred to as neuroleptic, may control mentalsymptoms of schizophrenia effectively. The commonly used antipsychoticdrugs first appeared in 1950s, such as chlorpromazine or haloperidol,have a main pharmacological effect of blocking central dopamine D₂receptor and are effective in the treatment of positive psychosissymptoms, but may cause extrapyramidal movement disorders, and areinvalid for negative symptoms and cognitive function damage,accompanying with many adverse reactions, also have greater toxicity oncardiovascular and liver with larger administration dose, andsignificant side effects, in order to overcome these shortcomings, since1980s, new antipsychotic drugs appeared, main pharmacological effect ofwhich is to block 5-HT_(2A) and D₂ receptors. The advantages of newantipsychotic drugs are that not only in the treatment of acuteexacerbation of psychiatric patients, but also in the treatment ofextrapyramidal symptoms and tardive dyskinesia, which have little sideeffects without the use of anticholinergic agents; tolerance andcompliance of the treatment are good; therapeutic effects in improvingpositive and negative symptoms and cognitive function are strong,adverse reactions of extrapyramidal system (EPS) may be less or may notbe caused, and endocrine adverse reactions may not be caused by theincrease of prolactin levels.

Risperidone as a representative of new antipsychotic drugs was developedby Janssen Pharmaceutica in Belgium in 1984, with the chemical name of3-[2-[4(6-fluoro-1,2-benzisoxazole-3-yl)1-piperidyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-α]pyrimidine-4-one, has as good therapeutic effect on positivesymptoms and negative symptoms of schizophrenia, and the incidence rateof extrapyramidal adverse reactions is low. A metabolite of risperidone,i.e., 9-hydroxy risperidone (paliperidone) has pharmacological effectssimilar to those of risperidone. Risperidone and 9-hydroxy risperidonetogether constitute the active ingredients of antipsychotic drugs.

Commonly used clinical dosage forms of risperidone comprise tablets,oral solutions, capsules, and orally disintegrating tablets, etc. Forcommon dosage forms of risperidone, drugs usually have to be taken everyday, which is difficult for about 75% of psychiatric patients. This isalso a very important factor contributing to deterioration during thetreatment.

In order to solve such problems, researchers have actively developedrisperidone long-acting sustained release preparations. For example,CN1137756, the entire content of which is incorporated herein byreference, disclosed a risperidone sustained release microspherecomposition prepared by using a polymer matrix material with a molecularweight of 100,000 to 300,000. Long-acting antipsychotic drug RisperidalConsta (Chinese name: HENGDE), which developed based on the technologyin CN1137756, came into market in August 2002. The product is preparedby encapsulating risperidone in a lactide-glycolide copolymer (PLGA)with a molecular weight of 150,000, suspended in a solution, andadministrated by intramuscular injection once every 2 weeks, thusavoiding the peak-valley concentration of daily administrationeffectively. However, only a small amount of drug in the preparation isreleased on the first day, followed by a drug release lag phase after 3weeks, and with the degradation of the microsphere skeleton, most ofdrugs are released in the 4th to 6th weeks [Chen Qinghua, Chen Gang, etal, pharmacokinetic characteristics and clinical application ofrisperidone long-acting injection, Chinese Pharmacy, 2006, 15 (15);1235-1238]. Therefore, while the drug is administrated to patients byinjection in the first 3 weeks, patients also need to rely on oralrisperidone tablets to achieve therapeutic effects, and subsequently theclinical use is not convenient and patient compliance is poor.

Chen Guoguang et al reported a risperidone microsphere compositionprepared by using PLGA (50:50, molecular weight of 30,000) with adrug-loading rate of 18%, by which a stable drug blood concentration maybe maintained in vivo for 5-20 days [Chen Guoguang, Tang Jun, et al,study on risperidone biodegradable microspheres, Journal of ChinaPharmaceutical University, 2006, 37 (6):512-515]. However, thedrug-loading rate of this microsphere composition is low, and is alsoaccompanied with a burst release when the drug-loading rate is low.

CN101653422, the entire content of which is incorporated herein byreference, disclosed a risperidone microsphere composition which maycause sustained release for more than 4 weeks, and the drug release lagphase was eliminated by improving the drug-loading rate (above 45%),substantially solve burst release problems. However, the patenapplication of CN 101653422 only verifies that the laboratory level (5 Lscale) may achieve the desired object. It has been found by theapplicant of the present invention that drug crystals were precipitatedout during the scaled-up production of risperidone microspheres providedin CN101653422, the preparation stability was poor, and in vivo releasebehavior of the microspheres will change substantially after long-termstorage.

As is well known, large-scale industrialized production has always beenthe bottleneck of the industrialization of the microsphere preparation,and therefore there is an urgent need to provide a formulation ofrisperidone microspheres that is stable in quality and suitable forlarge-scale industrialized production.

SUMMARY

The present disclosure provides a pharmaceutical microspherecomposition, containing an active ingredient and an uncappedpoly(lactide-co-glycolide), in which the active ingredient is selectedfrom risperidone or a salt thereof, and 9-hydroxy risperidone or a saltthereof; the uncapped poly(lactide-co-glycolide) consists of twocopolymers; a weight content of the active ingredient in thepharmaceutical composition is within a range from 10% to 60%,preferably, from 35% to 55%, more preferably, from 40% to 50%; and aweight content of the uncapped poly(lactide-co-glycolide) in thepharmaceutical composition is within a range from 40% to 90%,preferably, from 45% to 65%, more preferably, from 50% to 60%.

The microspheres as disclosed herein is: Small spherical orspherical-like particles consist of drug dissolved and (or) dispersedhomogeneously throughout a polymer material, with a particle sizeranging in 1-500μm, and generally prepared as suspensions for injection.

A lactide-glycolide copolymer is also referred to aspoly(lactide-co-glycolide), abbreviated as PLGA. As used herein, theterm “uncapped poly(lactide-co-glycolide)” refers topoly(lactide-co-glycolide) having a carboxyl terminal group, belowabbreviated as PLGA.

The two copolymers, i.e., the two PLGAs, are an uncapped PLGA with ahigh intrinsic viscosity of 0.4-0.9 dl/g, preferably, 0.45-0.8 dl/g,more preferably, 0.45-0.55 dl/g, and an uncapped PLGA, with a lowintrinsic viscosity of 0.1-0.35 dl/g, preferably, 0.1-0.3 dl/g, morepreferably, 0.2-0.3 dl/g. A weight ratio of the uncapped PLGA with thehigh intrinsic viscosity to the uncapped PLGA with the low intrinsicviscosity is (50-95):(5-50), preferably, (70-90):(10-30), morepreferably, 80:20. A molar ratio of lactide to glycolide in the uncappedPLGA with the high intrinsic viscosity is within a range from 65:35 to90:10, preferably, 75:25; and as molar ratio of lactide to glycolide inthe uncapped PLGA with the low intrinsic viscosity is within a rangefrom 50:50 to 75:25, preferably, 50:50.

The intrinsic viscosity of PLGA is determined by preparing an about 0.5%(w/v) solution of PLGA in chloroform, and determining the intrinsicviscosity of PLGA at 30° C. using a Cannon-Fenske glass capillaryviscometer.

The two PLGAs may also be a high molecular weight PLGA with a molecularweight of 50,000-145,000, preferably, 55,000-110,000, more preferably,55,000-85,000 and a low molecular weight PLGA with a molecular weight of4000 to 45,000, preferably, 4,000-35,000, more preferably,15,000-35,000. A weight ratio of the high molecular weight PLGA to thelow molecular weight PLGA is (50-95):(5-50), preferably,(70-90):(10-30), more preferably, 80:20. A molar ratio of lactide toglycolide in the high molecular weight PLGA is within a range from 65:35to 90:10, preferably, 75:25; and a molar ratio of lactide to glycolidein the low molecular weight PLGA is within a range from 50:50 to 75:25,preferably, 50:50. As used herein, the term “molecular weight” refers to“weight average molecular weight”, abbreviated as “molecular weight”.

For convenient description, hereinafter, the molar ratio of lactide toglycolide in PLGA and the intrinsic viscosity of PLGA are expressed in abracket after PLGA. For example, “PLGA (75/25, 0.5A)” refers to alactide-glycolide copolymer having an intrinsic viscosity of 0.5 dl/gand a carboxyl terminal group, in which a molar ratio of lactide toglycolide is 75:25.

Particularly, the preferred weight ratio of the uncapped PLGA (75/25,0.5A) with the high intrinsic viscosity to the uncapped PLGA (50/50,0.25A) with the low intrinsic viscosity in the present invention is80:20.

Specifically, in the microsphere composition of the present invention,the preferred weight content of risperidone is 45% and the weightcontent of uncapped PLGA is 55%, the weight ratio of the two PLGAs is80:20, the molecular weight of the two PLGAs are 55,000-85,000 and15,000-35,000, the intrinsic viscosity of the two PLGAs are 0.45-0.55dL/g and 0.2-0.3dL/g, and molar ratio of lactide to glycolide in the twoPLGAs are 75:25 and 50:50, respectively.

As used herein, a drug-loading rate refers to a practical drug-loadingrate, which is calculated by a formula: drug-loading rate=[amount ofdrug in microspheres/(amount of drug in microspheres+amount of polymerin microspheres)]×100%.

Risperidone or 9-hydroxy risperidone in the sustained releasemicrospheres of the present invention may be present in the form of asalt. An acid which will form a salt with risperidone or 9-hydroxyrisperidone comprises an inorganic acid, for example, halogen acid(e.g., hydrochloric acid or hydrobromic acid), nitric acid, sulfuric,acid or phosphoric acid; or an organic acid, for example, acetic acid,propionic acid, hydroxy acetic acid, 2-hydroxy propionic acid, pamoicacid, 2-oxo propionic acid, oxalic acid, malonic acid, succinic acid,2-butenedioic acid, methanesulfbnic acid, ethanesulfonic acid,benzenesulfonic acid or toluenesulfonic acid.

The risperidone sustained release microspheres of the present inventionmay be prepared by a conventional method, for example, anemulsion-solvent evaporation method, a spray drying method or a sprayextraction method, etc.

Emulsion-Solvent Evaporation Method

Risperidone or a salt thereof or 9-hydroxy risperidone or a salt thereofand PLGA are dissolved in a suitable organic solvent, the organicsolvent is injected into an aqueous solution prepared from a watersoluble polymer to perform dispersion emulsifying, the organic solventis evaporated, and the residue is washed and filtered to obtainmicrospheres. The organic solvent may be selected from halogenatedhydrocarbons (e.g., dichloromethane, chloroform, ethyl chloride,dichloromethane, or trichloroethane), ethyl acetate, ethyl formate,diethyl ether, cyclohexane, benzyl alcohol, or a combination thereof.The water soluble polymer may be selected from at least one of polyvinylalcohol (PVA), sodium carboxymethyl cellulose (CMC-Na), polyvinylpyrrolidone (PVP), sodium polymethacrylate and sodium polyacrylate, or acombination of two or more of them. The dispersion emulsifying may beperformed by mechanical stirring or by a static mixer.

Spray Drying Method

Risperidone or as salt thereof or 9-hydroxy risperidone or as saltthereof and PLGA are dissolved in a suitable organic solvent andfiltered, and a conventional spray drying method is used to preparemicrospheres. The organic solvent may be selected from dichloromethane,chloroform, ethyl acetate, diethyl ether, acetone, benzyl alcohol,glacial acetic acid, or a combination thereof.

Spray Extraction Method

Risperidone or a salt thereof or 9-hyd,roxy risperidone or as saltthereof and PLGA are dissolved in as suitable organic solvent to final asolution, and then the solution is sprayed into an organic nonsolvent(i.e., an organic solvent in which risperidone or a salt thereof or9-hydroxy risperidone or a salt thereof and PLGA are not dissolved) orwater, and extracted the solvent to form the microspheres. The organicsolvent may be selected from dichloromethane, chloroform, ethyl acetate,diethyl ether, acetone, benzyl alcohol, glacial acetic acid, or ascombination thereof. The organic nonsolvent may be selected frommethanol, ethanol, propanol, isopropanol, petroleum ether, alkane,paraffine, or a combination thereof.

The present disclosure further provides a use of the risperidonemicrospheres in preparation of antipsychotic drugs, in which a psychosiscomprises acute schizophrenia and chronic schizophrenia, significantpositive symptoms (e.g., hallucination, delusion, thought disorder,hostility, or suspicion and significant negative symptoms (e.g., slowresponse, emotional indifference, social indifference, or hypologia) ofother psychotic states, and affective symptoms (e.g., depression, guiltyfeeling, or anxiety) related to schizophrenia, preferably;schizophrenia, anxiety, depression, periodic headache, etc.

In another embodiment, the present disclosure provides a method oftreating psychosis by administering a formulation of risperidonemicrospheres described herein. The psychosis comprises acuteschizophrenia and chronic schizophrenia, significant positive symptoms(e.g., hallucination, delusion, thought disorder, hostility, orsuspicion) and significant negative symptoms (e.g., slow response,emotional indifference, social indifference, or hypologia) of otherpsychotic states, and affective symptoms (e.g, depression, guiltyfeeling, or anxiety) related to schizophrenia, preferably,schizophrenia, anxiety, depression, periodic headache, etc.

The microspheres according to an embodiment of the present disclosuremay be present in the form of a sterile powder. The sterile powder maycontain the risperidone microsphere composition and mannitol and may beprepared by washing the sustained release composition with water forinjection, transferring the sustained release composition to alyophilized plate, adding mannitol and an appropriate amount ofinjection water, placing the lyophilized plate in a lyophilizer forlyophilizing, subjecting the lyophilized product to screening andmixing, sterile subpackaging, and capping to obtain the sterile powder.Before administrating the drug to a patient, the sterile powder issuspended in an acceptable dispersion solvent. The dispersion solvent isselected from at least one of a suspending agent, a regulator, anisoosmotic adjusting agent, a surfactant, and water for injection. Thesuspending agent may he selected from at least one of sodiumcarboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone,sodium alginate, and glycerol. The isoosmotic adjusting agent may beselected from at least one of sodium chloride, glucose, mannitol, andglucitol. The surfactant is a nonionic surfactant, for example,polysorbate series (e.g., polysorbate 80 or polysorbate 60) or poloxamerseries (e.g., poloxamer 188).

The risperidone sustained release microsphere composition according toan embodiment of the present disclosure is usually administratedparenterally, for example, intramuscular injection, subcutaneousinjection, intradermal injection, intraperitoneal injection and so on.For a patient with a body weight of 60 kg, administration dose is12.5-1.50 mg every time, based on risperidone. That is, atherapeutically effective amount of the risperidone sustained releasemicrosphere composition is 0.2-2.5 mg risperidone/kg body weight,preferably, 0.4-1.7 mg risperidone/kg body weight.

The sustained release microsphere composition has the followingadvantages: 1) it provides immediate release after entering into a bodywithout drug release lag phase, in both high or low drug-loading; 2) itis conducive to scaled-up production (scale above 75 L) and without drugcrystals precipitating out during the production; 3) it is highlystable, and therefore in vivo release behavior will not change afterlong-term storage.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1-1 is a scanning electron microscope image of risperidonemicrospheres in CN101653422, in which drug crystals are precipitatedout.

FIG. 1-2 is a scanning electron microscope image of risperidonemicrospheres in Embodiment 6, in which no drug crystals are precipitatedout, which indicates that the risperidone microspheres according to anembodiment of the present disclosure is suitable for large-scaleindustrialized production.

FIG. 2 shows in vivo release blood drug concentration-time curves of arisperidone microsphere composition (prepared according to CN101653422)before and after being stored for 6 months, which indicates that the invivo drug release behavior of the risperidone microspheres inCN101653422 after being stored for 6 months changes substantially andthe quality of the risperidone microspheres disclosed in CN101653422 isnot stable.

FIG. 3 shows in vivo release blood drug concentration-time curves ofrisperidone microspheres in Embodiment 1 before and after being storedfor 6 months, which indicates that in vivo drug release behavior of therisperidone microspheres in Embodiment 1 after being stored for 6 monthsdoes not change substantially and the quality of the risperidonemicrospheres according to an embodiment of the present disclosure ismuch more stable.

FIG. 4 shows in vivo release blood drug concentration-time curves ofrisperidone microspheres in Embodiment 3 before and after being storedfor 6 months, which indicates that in vivo drug release behavior of therisperidone microspheres in Embodiment 3 after being stored for 6 monthsdoes not change substantially and the quality of the risperidonemicrospheres according to an embodiment of the present disclosure ismuch more stable.

FIG. 5 shows in vivo release blood drug concentration-time curves ofrisperidone microspheres Embodiment4 before and after being stored for 6months which indicates that in vivo drug release behavior of therisperidone microspheres in Embodiment 4 after being stored for 6 monthsdoes not change substantially and the quality of the risperidonemicrospheres according to an embodiment of the present disclosure ismuch more stable.

FIG. 6 shows in vivo release blood drug concentration-time curves ofrisperidone microspheres in Embodiment 6 before and after being storedfor 6 months, which indicates that in vivo drug release behavior of therisperidone microspheres in Embodiment 6 after being stored for 6 monthsdoes not change substantially and the quality of the risperidonemicrospheres according to an embodiment of the present disclosure ismuch more stable.

FIG. 7 shows in vivo release blood drug concentration-time curves ofrisperidone microspheres in Embodiment 7 before and after being storedfor 6 months, which indicates that in vivo drug release behavior of therisperidone microspheres in Embodiment 7 after being stored for 6 monthsdoes not change substantially and the quality of the risperidonemicrospheres according to an embodiment of the present disclosure ismuch more stable.

FIG. 8 shows in vivo release blood drug concentration-time curves ofrisperidone microspheres in Embodiment 9 before and after being, storedfor 6 months, which indicates that in vivo drug release behavior of therisperidone microspheres in Embodiment 9 after being stored for 6 monthsdoes not change substantially and the quality of the risperidonemicrospheres according to an embodiment of the present disclosure ismuch more stable.

FIG. 9 shows in vivo release blood drug concentration-time curves ofrisperidone microspheres in Test embodiment 2, which indicates that adrug may be still released immediately after entering into a body evenwhen the drug-loading rate of the risperidone microspheres according toan embodiment of the present disclosure as low as about 20%, without arelease lag phase.

DETAILED DESCRIPTION

As described herein, various embodiments are directed to pharmaceuticalcompositions, which comprise an active component selected fromrisperidone, a salt thereof, 9-hydroxy risperidone and a salt thereof;and a polymer blend comprising a first uncappedpoly(lactide-co-glycolide) and a second uncappedpoly(lactide-co-glycolide), wherein a weight content of the activecomponent in the pharmaceutical composition is within a range from 10%to 60%, preferably from 35% to 55%, more preferably from 40% to 50%; aweight content of the polymer blend in the pharmaceutical composition iswithin a range from 40% to 90%, preferably from 45% to 65%, morepreferably from 50% to 60%; and the pharmaceutical composition ispresent in the form of microspheres.

In the pharmaceutical composition of one embodiment of the presentdisclosure, the polymer blend consists of the first uncappedpoly(lactide-co-glycolide) and the second uncappedpoly(lactide-co-glycolide).

In the pharmaceutical composition of one embodiment of the presentdisclosure, the first uncapped poly(lactide-co-glycolide) has a highintrinsic viscosity of 0.4-0.9 dl/g, preferably 0.45-0.8 dl/g, morepreferably 0.45-0.55 dl/g, and the second uncappedpoly(lactide-co-glycolide) has a low intrinsic viscosity of 0.1-0.35dl/g, preferably 0.1-0.3 dl/g, more preferably 0.2-0.3 dl/g; and aweight ratio of the first uncapped poly(lactide-co-glycolide) to thesecond uncapped poly(lactide-co-glycolide) is (50-95):(5-50), preferably(70-90):(10-30), more preferably 80:20; and a molar ratio of lactide toglycolide in the first uncapped poly(lactide-co-glycolide) is within arange from 65:35 to 90:10, preferably 75:25; and a molar ratio oflactide to glycolide in the second uncapped poly(lactide-co-glycolide)is within a range from 50:50 to 75:25, preferably 50:50.

In the pharmaceutical composition of another embodiment of the presentdisclosure, the first uncapped poly(lactide-co-glycolide) has a weightaverage molecular weight of 50,000-145,000, preferably 55,000-110,000,more preferably 55000-85,000 and the second uncappedpoly(lactide-co-glycolide) has a weight average molecular weight of4,000 to 45,000, preferably 4,000-35,000, more preferably 15,000-35,000;and a weight ratio of the first uncapped poly(lactide-co-glycolide) tothe second uncapped poly(lactide-co-glycolide) is (50-95):(5-50),preferably (70-90):(10-30), more preferably 80:20; and a molar ratio oflactide to glycolide in the first uncapped poly(lactide-co-glycolide) iswithin a range from 65:35 to 90:10, preferably 75:25; and a molar ratioof lactide to glycolide in the second uncappedpoly(lactide-co-glycolide) is within a range from 50:50 to 75:25,preferably 50:50.

In the pharmaceutical composition of one preferred embodiment of thepresent disclosure, the weight content of risperidone is 45%, the weightcontent of the polymer blend is 55%, the weight ratio of the firstuncapped PLGA to the second uncapped PLGA is 80:20, the molecular weightof the first uncapped PLGA is 55,000˜85,000 and the molecular weight ofthe second uncapped PLGA is 15,000˜35,000, the intrinsic viscosity ofthe first uncapped PLGA is 0.45˜0.55 dL/g and the intrinsic viscosity ofthe second uncapped PLGA is 0.2˜0.3dL/g, and a molar ratio of lactide toglycolide in the first uncapped PLGA is 75:25 and a molar ratio of oflactide to glycolide in the second uncapped PLGA is 50:50.

In the pharmaceutical composition of one embodiment of the presentdisclosure, a salt of risperidone or 9-hydroxy risperidone is selectedfrom an inorganic acid salt and an organic acid salt; the inorganic acidsalt being selected from hydrochlorate, hydrobromate, nitrate, sulfateand phosphate; and the organic acid salt being selected from acetate,propionate, hydroxy acetate, 2-hydroxy propionate, pamoate, 2-oxopropionate, oxalate, malonate, succinate, 2-butenedioate,methanesulfonate, ethanesulfonate, benzenesulfonate andtoluenesulfonate.

The present disclosure further provides a use of any one of theabove-mentioned pharmaceutical compositions in preparation ofantipsychotics, wherein a psychosis comprises acute schizophrenia andchronic schizophrenia, significant positive symptoms and significantnegative symptoms of other psychotic states, and affective symptomsrelated to schizophrenia.

Another embodiment of the present disclosure provides a sustainedrelease microsphere formulation for injection, comprising any one of theabove-mentioned pharmaceutical compositions; and the microspheres aresuspended in a pharmaceutically acceptable dispersion solvent; thedispersion solvent is selected from a suspending agent, a pH regulator,an isoosmotic adjusting agent, a surfactant, water, and physiologicalsaline; and wherein the suspending agent is selected from sodiumcarboxymethyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone,sodium alginate, and glycerol; and wherein the isoosmotic adjustingagent is selected from sodium chloride, glucose, mannitol, and glucitol;and wherein the surfactant is a nonionic surfactant and is selected frompolysorbate series and poloxamer series.

The present disclosure will be further illustrated by the followingembodiments and test embodiments, which will not limit the scope of thepresent invention in any way.

Embodiment 1

72 g of PLGA (75/25, 0.52A) with a molecular weight of 74,000, 18 g ofPLGA (50/50, 0.25A) with a molecular weight of 25,000 and 110 g ofrisperidone were weighed and dissolved in 1000 ml of dichloromethanewith stirring to prepare a clear solution. The clear solution was addedinto a microsphere preparation kettle containing a 100 L PVA solution(0.5%) cooled to 6° C. by a peristaltic pump. A stirrer and ahomogenizer were started, and then the clear solution was homogeneouslyemulsified at 380 rpm for 1 min. Then, the rotation speed of thehomogenizer was reduced, and an organic solvent was evaporated for 3-5h. The residue was filtered with a screen, washed with deionized water,and lyophilized to obtain powdered microspheres. No crystals wereprecipitated out. The microspheres had a drug-loading rate of 45.9% andan encapsulation efficiency of 83.5%.

Embodiment 2

67.5 g of PLGA (75/25, 0.42A) with a molecular weight of 55,000, 7.5 gof PLGA (50/50, 0.25A) with a molecular weight of 25,000 and 75 g ofrisperidone were weighed and dissolved in 750 ml of dichloromethane withstirring to prepare a clear solution. The clear solution was added intoa microsphere preparation kettle containing a 75 L PVA solution (0.5%)cooled to 6° C., by a peristaltic pump. A stirrer and a homogenizer werestarted, and then the clear solution was homogeneously emulsified at 380rpm for 1 min. Then, the rotation speed of the homogenizer was reduced,and an organic solvent was evaporated for 3-5 h. The residue wasfiltered with a screen, washed with deionized water, and lyophilized toobtain powdered microspheres. No crystals were precipitated out. Themicrospheres had a drug-loading rate of 40.2% and an encapsulationefficiency of 80.4%.

Embodiment 3

56 g of PLGA (75/25, 0.90A) with a molecular weight of 125,000, 24 g ofPLGA (50/50, 0.25A) with a molecular weight of 25,000 and 120 g ofrisperidone were weighed and dissolved in 1000 ml of dichloromethanewith stirring to prepare a clear solution. The clear solution was addedinto a microsphere preparation kettle containing a 100 L PVA solution(0.5%) cooled to 6° C. by a peristaltic pump. A stirrer and ahomogenizer were started, and then the clear solution was homogeneouslyemulsified at 380 rpm for 1 min. Then, the rotation speed of thehomogenizer was reduced, and an organic solvent was evaporated for 3-5h. The residue was filtered with a screen, washed with deionized water,and lyophilized to obtain powdered microspheres. No crystals wereprecipitated out. The microspheres had a drug-loading rate of 51.5% andan encapsulation efficiency of 85.8%.

Embodiment 4

64.125 g of PLGA (75/25, 0.52A) with a molecular weight of 74,000, 3.375g of PLGA (50/50, 0.10A) with a molecular weight of 4,200 and 82.5 g ofrisperidone were weighed and dissolved in 750 ml of dichloromethane withstirring to prepare a clear solution. The clear solution was added intoa microsphere preparation kettle containing a 75 L PVA solution (0.5%)cooled to 6° C. by a peristaltic pump. A stirrer and a homogenizer werestarted, and then the clear solution was homogeneously emulsified at 380rpm for 1 min. Then, the rotation speed of the homogenizer was reduced,and an organic solvent was evaporated for 3-5 h. The residue wasfiltered with a screen, washed with deionized water, and lyophilized toobtain powdered microspheres. No crystals were precipitated out. Themicrospheres had a drug-loading rate of 45.5% and an encapsulationefficiency of 82.7%.

Embodiment 5

63 g of PLGA (75/25, 0.52A) with a molecular weight of 74,000, 27 g ofPLGA (50/50, 0.35A) with a molecular weight of 40,000 and 60 g ofrisperidone were weighed and dissolved 750 ml of dichloromethane withstirring to prepare a clear solution. The clear solution was added intoa microsphere preparation kettle containing a 75 L PVA solution (0.5%)cooled to 6° C. by a peristaltic pump. A stirrer and a homogenizer werestarted, and then the clear solution was homogeneously emulsified at 380rpm for 1 min. Then, the rotation speed of the homogenizer was reduced,and an organic solvent was evaporated for 3-5 h. The residue wasfiltered with a screen, washed with deionized water, and lyophilized toobtain powdered microspheres. No crystals were precipitated out. Themicrospheres had a drug-loading rate of 33.1% and an encapsulationefficiency of 82.8%.

Embodiment 6

42 g of PLGA (65/35, 0.55A) with a molecular weight of 85,000. 10.5 g ofPLGA (50/50, 0.25A) with a molecular weight of 25.000 and 97.5 g ofrisperidone were weighed and dissolved in 750 ml of dichloromethane withstirring to prepare a clear solution. The clear solution was added intoa microsphere preparation kettle containing a 75 L PVA solution (0.5%)cooled to 6° C. by a peristaltic pump. A stirrer and a homogenizer werestarted, and then the clear solution was homogeneously emulsified at 380rpm for 1 min. Then, the rotation speed of the homogenizer was reduced,and an organic solvent was evaporated for 3-5 h. The residue wasfiltered with a screen, washed with deionized water, and lyophilized toobtain powdered microspheres. No crystals were precipitated out. Themicrospheres had a drug-loading rate of 55.0% and an encapsulationefficiency of 84.6%.

Embodiment 7

57.75 g of PLGA (90/10, 0.45A) with a molecular weight of 67,000, 24.75g of PLGA (50/50, 0.25A) with a molecular weight of 25,000 and 67.5 g ofrisperidone were weighed and dissolved in 750 ml of dichloromethane withstirring to prepare a clear solution. The clear solution was added intoa microsphere preparation kettle containing a 75 L PVA solution (0.5%)cooled to 6° C. by a peristaltic pump. A stirrer and a homogenizer werestarted, and then the clear solution was homogeneously emulsified at 380rpm for 1 min. Then, the rotation speed of the homogenizer was reduced,and an organic solvent was evaporated for 3-5 h. The residue wasfiltered with a screen, washed with deionized water, and lyophilized toobtain, powdered microspheres, No crystals were precipitated out. Themicrospheres had a drug-loading rate of 35.8% and an encapsulationefficiency of 79.6%.

Embodiment 8

68.25 g of PLGA (85/15, 0.71A) with a molecular weight of 110,000, 36.75g of PLGA (50/50. 0.25A) with a molecular weight of 25,000 and 45 g ofrisperidone were weighed and dissolved in 750 ml of dichloromethane withstirring to prepare a clear solution. The clear solution was added intoa microsphere preparation kettle containing a 75 L PVA solution (0.5%)cooled to 6° C. by a peristaltic pump. A stirrer and a homogenizer werestarted, and then the clear solution was homogeneously emulsified at 380rpm for 1 min. Then, the rotation speed of the homogenizer was reduced,and an organic solvent was evaporated for 3-5 h. The residue wasfiltered with a screen, washed with deionized water, and lyophilized toobtain powdered microspheres. No crystals were precipitated out. Themicrospheres had a drug-loading rate of 23.9% and an encapsulationefficiency of 79.7%.

Embodiment 9

54 g of PLGA (75/25, 0.52A) with a molecular weight of 74,000, 13.5 g ofPLGA (75/25, 0.20A) with a molecular weight of 25,000 and 82.5 g ofrisperidone were weighed and dissolved in 750 ml of dichloromethane withstirring to prepare a clear solution. The clear solution was added intoa microsphere preparation kettle containing a 75 L PVA solution (0.5%)cooled to 6° C. by a peristaltic pump. A stirrer and a homogenizer werestarted, and then the clear solution was homogeneously emulsified at 380rpm for 1 min. Then, the rotation speed of the homogenizer was reduced,and an organic solvent was evaporated for 3-5 h. The residue wasfiltered with a screen, washed with deionized water, and lyophilized toobtain powdered microspheres. No crystals were precipitated out. Themicrospheres had a drug-loading rate of 45.3% and an encapsulationefficiency of 82.4%.

Embodiment 10

60 g of PLGA (85/15, 0.71A) with a molecular weight of 110,000, 60 g ofPLGA (50/50, 0.25A) with a molecular weight of 25,000 and 30 g ofrisperidone were weighed and dissolved in 750 ml of dichloromethane withstirring to prepare a clear solution. The clear solution was added intoa microsphere preparation kettle containing a 75 L PVA solution (0.5%)cooled to 6° C. by a peristaltic pump. A stirrer and a homogenizer werestarted, and then the clear solution was homogeneously emulsified at 380rpm for 1 min. Then, the rotation speed of the homogenizer was reduced,and an organic solvent was evaporated for 3-5 h. The residue wasfiltered with a screen, washed with deionized water, and lyophilized toobtain powdered microspheres. No crystals were precipitated out. Themicrospheres had a drug-loading rate of 13.9% and an encapsulationefficiency of 69.5%.

Embodiment 11

48 g of PLGA (75/25, 0.61A) with a molecular weight of 92,000, 12 g ofPLGA (65/35, 0.12A) with a molecular weight of 5,000 and 140 g ofrisperidone were weighed and dissolved in 1000 m of dichloromethane withstirring to prepare a clear solution. The clear solution was added intoa microsphere preparation kettle containing a 100 L PVA solution (0.5%)cooled to 6° C. by a peristaltic pump. A stirrer and a homogenizer werestarted, and then the clear solution was homogeneously emulsified at 380rpm for 1 min. Then, the rotation speed of the homogenizer was reduced,and an organic solvent was evaporated for 3-5 h. The residue wasfiltered with a screen, washed with deionized water, and lyophilized toobtain powdered microspheres. No crystals were precipitated out. Themicrospheres had a drug-loading rate of 60.6% and an encapsulationefficiency of 84.3%.

Embodiment 12

54 g of PLGA (75/25, 0.52A) with a molecular weight of 74,000, 13.5 g ofPLGA (50/50, 0.25A) with a molecular weight of 25,000 and 85.65 of9-hydroxy risperidone were weighed and dissolved in 750 ml ofdichloromethane with stirring to prepare a clear solution. The clearsolution was added into a microsphere preparation kettle containing a 75L PVA solution (0.5%) cooled to 6° C. by a peristaltic pump. A stirrerand a homogenizer were started, and then the clear solution washomogeneously emulsified at 380 rpm for 1 min. Then the rotation speedof the homogenizer was reduced, and an organic solvent was evaporatedfor 3-5 h. The residue was filtered with a screen, washed with deionizedwater, and lyophilized to obtain powdered microspheres. No crystals wereprecipitated out. The microspheres had a drug-loading rate of 45.9% andan encapsulation efficiency of 83.5%.

Embodiment 13

64.8 g of PLGA (75/25, 0.52A) with a molecular weight of 74,000, 16.2 gof PLGA (50/50, 0.25A) with a molecular weight of 25,000 and 192.6 g ofparnoic acid risperidone were weighed and dissolved in 750 ml ofdichloromethane with stirring to prepare a clear solution. The clearsolution was added into a microsphere preparation, kettle containing a75 L PVA solution (0.5%) cooled to 6° C. by a peristaltic pump. Astirrer and a homogenizer were started, and then the clear solution washomogeneously emulsified at 380 rpm for 1 min. Then, the rotation speedof the homogenizer was reduced, and an organic solvent was evaporatedfor 3-5 h. The residue was filtered with a screen, washed with deionizedwater, and lyophilized to obtain powdered microspheres. No crystals wereprecipitated out. The microspheres had a drug-loading rate of 45.9% andan encapsulation efficiency of 83.5%.

Embodiment 14

The microspheres obtained in Embodiment 1 were washed with water forinjection and transferred to a lyophilized plate. 4 g of mannitol and anappropriate amount of water were added, and the lyophilized plate wasplaced in a lyophilizer for lyophilizing. The lyophilized product wassubjected to screening and mixing, sterile subpackaging, and capping toobtain risperidone sustained release microspheres for injection.

Comparative Test 1 Scaled-Up Production of Risperidone MicrospheresDisclosed in CN101653422 (75L)

1) Test Materials

Risperidone, PLGA (75/25, 0.52A) with a molecular weight of 74,000

2) Method and Results

60 g of PLGA (75/25, 0.52A) with a molecular weight of 74,000 and 90 gof risperidone were weighed and dissolved in 750 ml of dichloromethanewith stirring to prepare a clear solution. The clear solution was addedinto a microsphere preparation kettle containing a 75 L PVA solution(0.5%) cooled to 6° C. by a peristaltic pump. A stirrer and ahomogenizer were started, and then the clear solution was homogeneouslyemulsified at 380 rpm for 1 min. Then, the rotation speed of thehomogenizer was reduced, and an organic solvent was evaporated for 3-5h. The residue was filtered with a screen, washed with deionized water,and lyophilized to obtain powdered microspheres. After observed by amicroscope, drug crystals were discovered, as shown in FIG. 1-1.

In contrast, the microspheres obtained in Embodiments 1-10 according tothe present disclosure, when observed by a microscope, showed no drugcrystals that precipitated out. FIG. 1-2 is a scanning electronmicroscope image of risperidone microspheres in Embodiment 6.

The results indicate that the risperidone microspheres according to anembodiment of the present disclosure are more suitable for large-scaleindustrialized production.

Comparative Test 2 Stability Test of an Embodiment of the PresentDisclosure as Compared with CN 101653422

1) Test Materials

Test Drugs:

The present disclosure: the risperidone microspheres obtained inEmbodiments 1, 3, 4, 6, 7, 9 were stored for 0 month and 6 monthsrespectively.

CN101653422: the risperidone microspheres obtained in Embodiment 3 inCN101653422 was stored for 0 month and 6 months, 4.0 g of PLGA (75/25,0.52A) with a molecular weight of 74,000 and 6.0 g of risperidone wereweighed and dissolved in 50 ml of dichloromethane with stirring toprepare a clear solution. The clear solution was added into amicrosphere preparation kettle containing a 5000 ml PVA solution (0.5%)cooled to 6° C. with high-speed stirring by a peristaltic pump, anddispersion emulsified at 1000 rpm for 1 min. Then, the rotation speedwas adjusted to 300 rpm, the rotation speed of a stirring paddle was 150rpm, and any organic solvent was removed by evaporation for 6 h. Theresidue was filtered with a screen, washed with deionized water 5 times,and lyophilized to obtain powdered microspheres. The microspheres had adrug-loading rate of 50.7% and an encapsulation efficiency of 84.5%.

Test Animals: 56 healthy beagles dogs, 4 dogs in each group,28-female-28-male, with a body weight of 9.5-10.5 kg.

Test Instruments: an API 4000 triple quadrupole tandem mass spectrometerequipped with an ion spray ionization source and an Analyst 1.4 dataprocessing software, U.S., Applied Biosystem company: Agilent 1100 highperformance liquid chromatograph.

2 Method and Results

The test animals were randomly divided into 2 groups (0-month group and6-month group) with 4 dogs in each group, a dose of 1.5 mg/kg (based onrisperidone) was administrated by intramuscular injection on eachbeagle, and after administrating for 0 h, 1 h, 3 h, 6 h, 1 d, 2 d, 3 d,5 d, 7 d, 9 d, 11 d, 14 d, 16 d, 18 d, 21 d, 23 d, 25 d, and 28 d, 3 mlof blood was sampled via the forelimb vein of each beagle, placed in theheparinization centrifuge tube immediately, and centrifugated for 10 min(3600 rpm ). A plasma was separated, and stored in a refrigerator at−37° C. to be measured. Drug blood concentrations of risperidone and ametabolite thereof, i.e., 9-hydroxy risperidone, in the plasma weremeasured respectively, and the results were shown in Table 1 and FIGS.2-8.

It may be seen from the results that there was substantial changes inthe in vivo drug release behavior of the risperidone microspheresdisclosed in CN101653422 after being, stored for 6 months; but the invivo drug, release behavior of the risperidone microspheres according toan embodiment of the present disclosure after being stored for 6 mouthsdoes not change substantially due to improved stability.

TABLE 1 Drug blood concentrations (ng/mL) at different time after themicrospheres according to an embodiment of the present disclosure and inCN101653422 after stored for 6 months were administrated byintramuscular injection on each beagle Time Embodiment 1 Embodiment 3Embodiment 4 Embodiment 6 (day) 0 month 6 month 0 month 6 month 0 month6 month 0 month 6 month 0 0 0 0 0 0 0 0 0 0.042 2.619 2.593 2.126 2.7392.635 2.817 4.792 4.469 0.125 1.665 2.326 1.156 1.512 1.049 1.55 1.1862.202 0.25 1.79 3.449 1.209 2.665 1.174 2.673 3.311 3.325 1 1.268 1.4060.786 0.607 0.652 0.630 5.662 1.282 2 1.589 1.860 1.096 1.058 0.9731.084 3.110 4.739 3 1.73 3.928 1.205 3.122 1.114 6.569 4.265 7.221 510.561 8.32 10.262 7.536 9.945 7.544 10.082 10.298 7 16.548 19.78913.099 15.621 15.932 16.336 16.069 15.223 9 12.837 18.237 12.337 17.43313.229 15.623 13.366 16.275 11 10.125 14.214 9.625 13.414 9.509 13.4389.646 14.09 14 13.641 17.38 13.114 16.33 13.025 16.604 13.162 17.256 1612.326 12.427 11.865 11.627 11.71 11.651 11.847 11.301 18 13.582 14.19513.006 13.656 12.966 13.419 13.103 14.071 21 8.48 6.581 7.980 5.7817.864 5.805 5.007 6.457 23 6.155 5.027 5.565 5.227 5.539 4.251 1.6762.903 25 3.004 1.866 2.069 1.066 2.388 1.090 1.230 1.742 28 0.713 1.3860.231 0.583 0.097 0.610 0.234 0.213 Time Embodiment 7 Embodiment 9CN101653422 (day) 0 month 6 month 0 month 6 month 0 month 6 month 0 0 00 0 0 0 0.042 2.098 2.661 4.496 4.112 2.919 2.369 0.125 1.097 1.434 0.891.845 2.014 1.628 0.25 1.15 1.562 3.015 2.968 2.795 1.76 1 0.727 0.5295.366 0.925 1.213 1.138 2 1.037 0.98 2.814 4.382 1.497 0.804 3 1.1463.044 3.969 5.621 1.8595 0.62 5 9.203 7.458 9.786 9.941 7.2195 5.335 78.268 12.361 15.773 14.866 15.9145 5.314 9 12.278 10.695 13.07 11.90214.361 8.079 11 9.566 13.336 9.35 10.356 12.0665 7.719 14 13.055 11.25212.866 13.231 16.868 13.095 16 11.806 11.549 11.551 10.944 11.955 17.67918 12.947 13.578 10.32 9.967 12.998 20.781 21 7.921 5.703 4.711 6.16.044 18.068 23 5.506 5.149 1.38 2.546 3.026 9.215 25 3.056 2.988 0.9341.385 1.727 4.123 28 1.265 1.658 0.063 0.123 1.3495 2.136

Comparative Test 3 Release Results of Risperidone Microspheres of thePresent Disclosure with Different Drug-Loading Rates in Dog BodiesCompared with Release Results of Risperidone Microspheres in CN101653422with Different Drug-Loading Rates in Dog Bodies

1) Test Materials

Test Drugs:

The present disclosure: the risperidone microspheres with drug-loadingrates of 13.9%, 23.9%, 33.1%, 40.2% obtained in Embodiments 2, 5, 8, 10respectively.

CN101653422: the risperidone microspheres with drug-loading rates of45.5%, 40.3%, 35.6% obtained according to Embodiments 7-9 of CN101653422, respectively.

Test Animals: 24 healthy beagles dogs, 4 dogs in each group,12-femate-12-male, with a body weight of 9.5-10.5 kg.

Test instruments: the same as those in Test Embodiment 2.

2) Method and Results

The test method is the same as that in Test Embodiment 2.

The test results were shown in Table 2 and FIG. 9.

The results show that, for the risperidone microspheres in CN101653422,the drug may not be released immediately after entering into a body whenthe drug-loading rate is below 45%, i.e., there is a release lag phase.In contrast, for the risperidone microspheres according to an embodimentof the present disclosure, the drug may still be released immediatelyafter entering into a body even when the drug-loading rate of is as lowas about 10%, i.e., there is not a release lag phase.

TABLE 2 Drug blood concentrations (ng/mL) at different times after themicrospheres according to an embodiment of the present disclosure and inCN101653422 were administrated by intramuscular injection on each beagleDrug-loading rate The present disclosure CN101653422 Time (day) 13.9%23.9% 33.1% 40.2% 35.6% 40.3% 45.5% 0 0 0 0 0 0 0 0 0.042 1.011 1.0281.059 1.428 0.635 0.233 3.023 0.125 2.365 2.846 2.991 1.367 0.621 0.4122.566 0.25 1.652 1.899 1.051 1.423 0.619 0.411 2.651 1 2.368 2.486 2.6283.577 0.617 0.405 3.553 2 2.356 2.786 2.938 2.509 0.539 0.455 4.065 32.669 2.895 3.047 3.416 0.432 0.636 4.322 5 6.659 7.296 8.104 8.4730.612 1.323 7.587 7 11.026 12.018 12.169 12.538 1.321 6.036 14.852 914.011 14.058 15.179 15.548 2.365 7.229 19.286 11 13.102 13.022 15.46913.838 5.691 11.292 16.963 14 13.561 12.804 17.697 15.838 13.665 20.55216.663 16 14.667 15.556 17.707 18.076 29.053 30.026 18.337 18 19.22318.696 17.808 17.102 30.658 29.199 20.544 21 14.003 13.085 10.822 10.19120.511 15.236 12.802 23 12.325 9.236 8.407 6.776 10.664 11.813 7.801 259.166 8.805 6.957 5.364 6.366 5.221 4.503 28 6.076 5.016 4.196 4.5354.112 2.323 2.209

What is claimed is:
 1. Microspheres for sustained release of an activeagent comprising: an active component selected from the group consistingof risperidone, 9-hydroxy risperidone, a salt of risperidone, and a saltof 9-hydroxy risperidone; and a polymer blend consisting essentially ofa first uncapped poly(lactide-co-glycolide) and a second uncappedpoly(lactide-co-glycolide), wherein the first uncappedpoly(lactide-co-glycolide) has an intrinsic viscosity of 0.4-0.9 dl/gand a molar ratio of lactide to glycolide of 65:35 to 90:10; and whereinthe second uncapped poly(lactide-co-glycolide) has an intrinsicviscosity of 0.1-0.35 dl/g and a molar ratio of lactide to glycolide of50:50 to 75:25.
 2. The microspheres of claim 1, wherein the molar ratioof lactide to glycolide in the first uncapped poly(lactide-co-glycolide)is 75:25; and wherein the molar ratio of lactide to glycolide in thesecond uncapped poly(lactide-co-glycolide) is 50:50.
 3. The microspheresof claim 1, wherein a weight ratio of the first uncappedpoly(lactide-co-glycolide) to the second uncappedpoly(lactide-co-glycolide) is in a range from 50:50 to 95:5.
 4. Themicrospheres of claim 1, wherein the first uncappedpoly(lactide-co-glycolide) has a molecular weight from 50,000 to145,000; and wherein the second uncapped poly(lactide-co-glycolide) hasa molecular weight from 4,000 to 45,000.
 5. The microspheres of claim 1,wherein the active agent is in an amount of from 10% to 60% based on atotal weight of the microspheres.
 6. Microspheres for sustained releaseof an active agent comprising: an active agent selected from the groupconsisting of risperidone, 9-hydroxy risperidone, a salt of risperidone,and a salt of 9-hydroxy risperidone; and a polymer blend consistingessentially of a first uncapped poly(lactide-co-glycolide) and a seconduncapped poly(lactide-co-glycolide); wherein the first uncappedpoly(lactide-co-glycolide) has a molecular weight from 50,000 to 145,000and a molar ratio of lactide to glycolide in a range from 65:35 to90:10; wherein the second uncapped poly(lactide-co-glycolide) has amolecular weight from 4,000 to 45,000 and a molar ratio of lactide toglycolide in a range from 50:50 to 75:25.
 7. The microspheres of claim6, wherein the first uncapped poly(lactide-co-glycolide) has a molecularweight from 55,000 to 110,000; and wherein the second uncappedpoly(lactide-co-glycolide) has a molecular weight from 15,000 to 35,000.8. The microspheres of claim 6, wherein the molar ratio of lactide toglycolide in the first uncapped poly(lactide-co-glycolide) is 75:25; andwherein the molar ratio of lactide to glycolide in the second uncappedpoly(lactide-co-glycolide) is 50:50.
 9. The microspheres of claim 6,wherein a weight ratio of the first uncapped poly(lactide-co-glycolide)to the second uncapped poly(lactide-co-glycolide) is in a range from50:50 to 95:5.
 10. The microspheres of claim 6, wherein the firstuncapped poly(lactide-co-glycolide) has an intrinsic viscosity of0.4-0.9 dl/g; and wherein the second uncapped poly(lactide-co-glycolide)has an intrinsic viscosity of 0.1-0.35 dl/g.
 11. The microspheres ofclaim 6, wherein the active agent is in an amount of from 10% to 60%based on a total weight of the microspheres.
 12. Microspheres forsustained release of an active agent comprising: an active agentselected from the group consisting of risperidone, 9-hydroxyrisperidone, a salt of risperidone, and a salt of 9-hydroxy risperidone;and a polymer blend comprising a first uncappedpoly(lactide-co-glycolide) and a second uncappedpoly(lactide-co-glycolide); wherein the first uncappedpoly(lactide-co-glycolide) has a molecular weight from 55,000 to110,000, an intrinsic viscosity of 0.4-0.9 dl/g, and a molar ratio oflactide to glycolide in a range from 65:35 to 90:10; wherein the seconduncapped poly(lactide-co-glycolide) has a molecular weight from 15,000to 35,000, an intrinsic viscosity of 0.1-0.35 dl/g, and a molar ratio oflactide to glycolide in a range from 50:50 to 75:25; and wherein aweight ratio of the first uncapped poly(lactide-co-glycolide) to thesecond uncapped poly(lactide-co-glycolide) is in a range from 50:50 to95:5, such that lactide is a major monomer component compared toglycolide of the polymer blend.
 13. The microspheres of claim 12,wherein the active agent is in an amount of from 10% to 60% based on atotal weight of the microspheres.
 14. The microspheres of claim 13,wherein no crystals of the active agent are precipitated on the surfacesof the microspheres.
 15. A pharmaceutical formulation for injection intoa patient in need, comprising: the microspheres of claim
 1. 16. A methodof treating a psychosis comprising: administering parenterally atherapeutically effective amount of the pharmaceutical formulation ofclaim 15 to a patient in need.
 17. The method of claim 16, wherein theadministrating method is intramuscular injection, subcutaneousinjection, intradermal injection, or intraperitoneal injection.
 18. Themethod of claim 16, wherein each administration dose provides 12.5 to150 mg of risperidone.
 19. The method of claim 16, wherein thetherapeutically effective amount is 0.2 to 2.5 mg risperidone per kg ofbody weight.
 20. The method of claim 16, wherein the therapeuticallyeffective amount is 0.4 to 1.7 mg risperidone per kg of body weight. 21.A method of treating psychosis in a patient in need thereof, the methodcomprising: administering parenterally to the patient a therapeuticallyeffective amount of a pharmaceutical formulation comprising a pluralityof microspheres including (1) an active component selected from thegroup consisting of risperidone, 9-hydroxy risperidone, a salt ofrisperidone, and a salt of 9-hydroxy risperidone; and (2) a polymerblend consisting essentially of a first uncappedpoly(lactide-co-glycolide) and a second uncappedpoly(lactide-co-glycolide), wherein the first uncappedpoly(lactide-co-glycolide) has an intrinsic viscosity of 0.4-0.9 dl/gand a molar ratio of lactide to glycolide of 65:35 to 90:10; wherein thesecond uncapped poly(lactide-co-glycolide) has an intrinsic viscosity of0.1-0.35 dl/g and a molar ratio of lactide to glycolide of 50:50 to75:25, and the pharmaceutical formulation releases the active componentin a sustained manner for a period of up to 28 days.
 22. The method ofclaim 21 wherein the plurality of microspheres comprise 10% - 60% of theactive component based on the total weight of the microspheres.